Clinical and functional study of two de novo variations of CDKL5 gene.

ABSTRACT

The cyclin-dependent kinase like 5 (CDKL5) gene variation is X-linked dominant and is associated with type 2 developmental and epileptic encephalopathy (DEE). Although numerous cases of CDKL5 have been reported, there is limited discussion regarding functional verification. We described two children with DEE caused by de novo variations of CDKL5 gene, analyzed their clinical manifestations, and performed genetic testing on their gene variation sites. The two cases presented with tonic seizures followed by epileptic spasms, indicative of refractory epilepsy. Physical examination revealed abnormal facial features, including wide eye distance, low nose base, and high nose bridge. Both cases exhibited developmental disabilities. Cranial magnetic resonance imaging (MRI) showed widening of the bilateral frontotemporal extracerebral space. Genetic testing identified variations at the gene sites c.463 + 4A > G (splicing) and c.1854_1861delCAAAGTGA (p.D618Efs*18). Minigene experiments further confirmed that the intronic variation c.463 + 4A > G (splicing) disrupted splicing, leading to protein truncation. CDKL5 gene variation can lead to DEE, and intron variation site c.463 + 4A > G (splicing) can cause protein truncation, which is a pathogenic variation.